The inflammatory cytokine IL is an additional factor that ha

The inflammatory cytokine IL-6 is an additional factor that has been hypothesized to contribute to epinephrine-mediated repression of drug detoxifying proteins such as CYP3A4 (Aninat et al., 2008). Indeed, this CYP is well-known to be repressed by IL-6 (Dickmann et al., 2011) and epinephrine has previously been shown to trigger IL-6 secretion in HepaRG cell cultures, which appeared to be fully functional, as demonstrated by the concomitant secretion of CRP, a well-established target of IL-6 (Aninat et al., 2008). IL-6 is however unlikely to be involved in epinephrine-mediated changes of transporter expression because such changes were not correlated to those caused by the cytokine. Moreover, the JAK1/2 inhibitor ruxolitinib, which counteracted the effects of IL-6 such as CRP up-regulation through inhibiting the IL-6 receptor-downstream JAK/STAT pathway, failed to prevented OATP1B1, OATP2B1, OAT2 and OAT7 repression caused by epinephrine. Putative relevance of hepatic drug transporter alterations caused by epinephrine, and beyond, by marketed drugs acting as β2-ADR agonists like fenoterol or salbutamol, in terms of possible drug-drug interactions (DDIs), is most likely a key issue that has to be considered. In addition, modulation of transporter expression levels by physiological or pharmacological β2-ADR stimulators could contribute to inter-individual variability in disposition of transporter substrates. It is however noteworthy that no major alteration of drug pharmacokinetics has been associated with increased plasma concentrations of epinephrine, that occurs in response to stress, during diseases like pheochromocytoma or after the therapeutic administration of the catecholamine, notably for the treatment of wh4 or cardiac arrest. In the same way, to the best of our knowledge, the use of β2-ADR agonists has not been reported to result in possible notable DDIs involving drugs well-known to be handled by hepatic transporters like the cholesterol-lowering statins (substrates for OATPs) (Rodrigues, 2010) or the antidiabetic metformine (substrate for OCT1) (Koepsell, 2015). Such data therefore suggest that putative regulation of in vivo hepatic transporter expression due to epinephrine or β2-ADR stimulants is unlikely to cause major DDI. However, this conclusion should be substantiated by complementary and more complete investigations on this issue. Along the same line, whether the clinical use of β-ADR blockers may perturb physiological epinephrine-related regulation of hepatic transporters remains to be determined. Overall, it may nevertheless be hypothesized that transporter-related DDIs are likely primarily due to full blockage of transport activity by DDI perpetrators, that directly and physically interact with drug transporters (Endres et al., 2006, Giacomini et al., 2010). The numerous reported examples of established clinical DDIs strongly argue in favor of this hypothesis (DeGorter et al., 2012, Konig et al., 2013). Xenobiotic-mediated down-regulations of transporters, that commonly result in decrease, but not full abolition of drug transporter expression (Jigorel et al., 2006, Le Vee et al., 2013a), may thus fail to trigger major DDIs, probably because of notable basal remaining transport activity. This may explain why the characterization of potential direct drug transporter inhibition, and not that of drug transporter expression regulation, is the first goal of preclinical transporter studies recommended by drug regulatory agencies during the pharmaceutical development of new molecular entities (Liu and Sahi, 2016).
Acknowledgments
Introduction α2-Adrenergic agonists are valuable adjuncts for managing various clinical conditions including hypertension, glaucoma, muscle spasticity, and behavior disorders [5]. They are also widely used as anesthetics in perioperative settings for induction of anxiolysis, maintenance of sedation, and management of pain [4], [10]. More recently, these agents also show the capacity to attenuate neurological deficits following cerebral ischemia [7], [18], [19], [20].